Biologic Effects of Anti-Ganglioside Antibodies

抗神经节苷脂抗体的生物学效应

• 批准号: 8874311
• 负责人: KAZIM A SHEIKH
• 金额: $ 33.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874311
• 关键词: Acute; Affect; Affinity; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen-Antibody Complex; Autoantibodies; Autoimmune Process; Autoimmune Responses; Axon; Binding; CD209 gene; Cell surface; Cell-Mediated Cytolysis; Cells; Complex; Data; Dependency; Development; Disease; Fab Immunoglobulins; Failure; Fc Immunoglobulins; Fc Receptor; Fractionation; Fucose; Gangliosides; Goals; Guillain-Barré Syndrome; Health; Human; IgG Receptors; Immune; Immune system; Immunoglobulin G; Immunologic Receptors; In Vitro; Individual; Inflammation; Injury; Intravenous Immunoglobulins; Lectin; Left; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Microglia; Minor; Modeling; Multiple Sclerosis; Natural regeneration; Nerve; Nerve Crush; Neuroglia; Neurologic; Neurons; Neuropathy; Paralysed; Pathogenicity; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System; Poliomyelitis; Polysaccharides; Population; Pre-Clinical Model; Recombinants; Recovery; Recruitment Activity; Research; Role; Schwann Cells; Severity of illness; Sialic Acids; Site; Specificity; Structure; Surface Plasmon Resonance; Syndrome; Testing; Therapeutic; Tissues; Transgenic Mice; Transplantation; antibody-dependent cell cytotoxicity; axon regeneration; base; comparative efficacy; glycosylation; in vivo; inhibiting antibody; injured; macrophage; nerve injury; parent grant; prevent; reinnervation; repaired; role model; sialylation

DESCRIPTION (provided by applicant): After the near eradication of polio, Guillain-Barre syndrome (GBS) is the commonest cause of acute flaccid paralysis. Anti-ganglioside/glycan antibodies (Abs) are the most frequently recognized autoimmune responses in immune neuropathies grouped under the term GBS. Despite the availability of two immunomodulatory therapies, a significant proportion of patients are left with permanent neurologic sequelae. Patients with neurologic sequelae almost always have failure of axon regeneration and target reinnervation. Several studies indicate that specific anti-glycan Abs associate with poor recovery. Our group examined the effects of anti- glycan Abs on peripheral nerve repair and found these Abs inhibit regeneration of injured axons in preclinical models. The overall goals of this translational project are to study mechanisms underlying pathobiologic effects of anti-ganglioside Abs on axon regeneration and to develop strategies that could prevent the deleterious effects of anti-glycan Abs on nerve repair. Our preliminary results show that specific activating Fc-gamma receptors (Fc?Rs) particularly on macrophages recruited in the injured nerves are key determinants of Ab-mediated inhibition of nerve repair. Further, glycosylation of anti-ganglioside Abs is critical in their interactions with Fc?Rs and deglycosylation of anti-glyca Abs suppresses their inhibitory effects on nerve repair. Further, sialylated- fraction of human intravenous immunoglobulins (sIVIG), a minor component of IVIG, suppresses Ab-mediated inhibition of axon regeneration. We hypothesize that anti-glycan Abs bind to gangliosides on neural cell surfaces to form immune complexes on the proximal tips of injured axons and these in turn bind to specific activating Fc?Rs expressed by adjacent glial cells to induce tissue inflammation affecting axon regeneration. Furthermore, IgG Fc interactions with innate immune receptors are critically dependent on the IgG glycosylation and this glycosylation status can be manipulated (on pathogenic Abs and IVIG) to alter anti- ganglioside Ab- or IVIG-mediated effects. This renewal application will test these hypotheses by the following specific aims: Aim 1 will examine the role of specific Fc?Rs and glial cells expressing Fc?Rs in mediating nerve injury; Aim 2 will examine the role of N-glycan structures, carried by anti-glycan Abs, in their interactions with Fc?Rs to induce inflammation; and Aim 3 will examine the role of Fc/IgG sialylation as determinants of IVIG efficacy via the so-called 'DC-SIGN-Th2' anti-inflammatory pathway. These translational and 'proof of principle' studies have pathobiologic and therapeutic implications for failure of axon regeneration particularly that seen after immune insults/inflammation in autoimmune conditions like immune neuropathies and multiple sclerosis where failure of axonal repair is central to severity of the disease and recovery.

描述（由申请人提供）：在近乎根除脊髓灰质炎之后，Guillain-Barre综合征（GBS）是急性脆性瘫痪的最常见原因。抗葡萄糖剂/聚糖抗体（ABS）是术语GBS术语的免疫神经病中最常见的自身免疫反应。尽管有两种免疫调节疗法的可用性，但很大一部分患者仍具有永久性神经系统后遗症。神经系统后遗症的患者几乎总是会导致轴突再生和靶向连接失败。几项研究表明，特定的抗聚糖ABS与恢复差不良。我们的小组检查了抗聚糖ABS对周围神经修复的影响，并发现临床前模型中这些ABS抑制受伤的轴突的再生。该翻译项目的总体目标是研究抗ganglioside abs对轴突再生的病理生物学影响的基础机制，并制定可以防止抗聚糖ABS对神经修复的有害影响的策略。我们的初步结果表明，特别是在受伤神经中募集的巨噬细胞上，特定的激活FC-gamma受体（FC？rs）是AB介导的神经修复抑制作用的关键决定因素。此外，抗甘肽剂ABS的糖基化在与Fc？rs的相互作用中至关重要，抗Glyca ABS的脱糖基抑制了它们对神经修复的抑制作用。此外，IVIG的次要成分（SIVIG）的人类静脉免疫球蛋白（SIVIG）的含量分数抑制了AB介导的轴突再生的抑制作用。我们假设抗聚糖ABS与神经细胞表面上的神经节苷脂结合，以在受伤的轴突的近端尖端形成免疫复合物，而这些复合物与相邻神经胶质细胞表达的特定激活Fc？rs结合，以诱导影响轴突再生的组织炎症。此外，IgG FC与先天免疫受体的相互作用至关重要取决于IgG糖基化，并且可以操纵这种糖基化状态（在致病性ABS和IVIG上）以改变抗神经节苷脂AB-或IVIG介导的效果。这种续订应用将通过以下特定目的检验这些假设：目标1将检查表达Fc rs的特定FC和神经胶质细胞在介导神经损伤中的作用； AIM 2将检查反聚糖ABS携带的N-聚糖结构的作用，它们在与FC rs的相互作用中诱发炎症。 AIM 3将通过所谓的“ DC-SIGN-TH2”抗炎途径来研究FC/IgG溶解度作为IVIG疗效的决定因素。这些转化和“原理证明”研究对轴突再生的失败具有病原体和治疗意义，尤其是在自身免疫性疾病（如免疫神经病）和多发性硬化症（轴突修复失败的疾病严重程度和疾病严重性和康复严重程度的核心）中，在免疫损伤/炎症之后看到的。 。